In order to accomplish our goals as defined above, we have developed and initiated a clinical protocol with the following primary objectives: 1. Clinical evaluation of oral manifestations in patients with immune dysfunction. 2. Characterization of oral immune response in patients with monogenic immune defects. 3. Characterization of the oral microbiome in patients with monogenic immune defects. ORAL MICROBIOME STUDIES Oral micobiome studies will characterize the bacterial colonization in the oral cavity in patients with monogenic defect as compared to healthy subjects. STUDIES OF ORAL IMMUNE MECHANISMS The oral cavity is a unique environment for studying mucosal host defenses. Due to its accessibility we can non-invasively sample not only the bacteria on the tooth surface associated with health and disease but also the gingival crevicular fluid (an exudate from the periodontal pocket that contains locally produced immune mediators). Additionally, with minimally invasive procedures we can remove oral/gingival tissues to study the cellular composition, expression and production of immune mediators as well as engagement of signaling pathways that mediate health and disease in the oral cavity. We are focusing our initial studies on a patient population with a known disruption in the differentiation of Th17 cells known as the Hyper IgE syndrome, HIES. HIES is linked to a dominant negative STAT3 mutation. STAT3 regulates a wide variety of downstream targets, which differ depending on cell type. It is involved in inflammation, cell growth and differentiation, and even malignant transformation. STAT3 is activated by not only the interleukin IL 6 family, but also the IL-10 family, interferons (IFN), granulocyte colony-stimulating factor (G-CSF), and leptin among others. STAT3 is also key in the differentiation of Th17 cells, through the signaling of IL-23. Hence, the development of Th17-type inflammatory cells is deficient in patients with HIES. This patient population provides a unique opportunity to be able to study not only the role of STAT3 in human disease but also the contribution of Th17 cells in human immune homeostasis and pathology. We are currently clinically evaluating and characterizing the oral immune response and oral microbiome of the HIES patient cohort of the NIH> 40 patients.